Long Story Short - Searching for an effective RAS inhibitor, the Holy Grail of cancer treatment

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Drugging
the Undruggable: The War Against RAS Oncoproteins

(Note: companies that could be impacted by the content of this article are listed at the base of the story (desktop version). This article uses third-party references to provide a bullish, bearish and balanced point of view; sources listed in the "Balanced" section)The RAS pathway is one of the most frequently dysregulated pathways in cancer. Approximately 30% of tumors harbor activating RAS gene mutations. There are three main isoforms of oncogenic RAS: KRAS, HRAS and NRAS. Among these genes, KRAS is the most frequently mutated (~90% of pancreatic cancers, ?35% of colon cancers). In comparison, NRAS and HRAS are mutated in a lesser number of cancer patients (15% of melanomas and 4% of head and neck cancer patients).The RAS protein family consists of low molecular weight guanosine 5?-triphosphate (GTP), a building block of protein synthesis. GTP-binding proteins orchestrate a variety of cellular signaling networks, which are essential to regulate a variety of cellular functions including cell proliferation, differentiation, and cell survival. The three RAS proteins (N-RAS, H-RAS and K-RAS) oscillate between an active (GTP-bound) and an inactive (GDP-bound) state. When RAS genes are mutated (typically at codon 12, 13 or 61), RAS proteins are constitutively activated (i.e. continuously binding to GTP), which induces a pro-tumorigenic state characterized by unregulated cell proliferation and resistance to apoptosis (i.e. evading death signals). Constitutively activated RAS proteins trigger downstream signaling responsible for phenotypic traits known as hallmark of cancer including:

aberrant cell proliferation

resistance to apoptosis

increase in migration, cell invasion and metastasis to different tissues

escaping the anti-tumoral immune response

The phenotype of many cancer cells is determined by RAS-dependent aberrant signal transduction pathways involving various oncogenic proteins acting downstream of RAS (Exhibit 1).The high mutational rate of RAS genes in cancer patients, combined with the fundamental role of RAS proteins in cancer biology, makes the RAS family of oncoproteins a primary therapeutic target. Since its discovery in 1982, both academia and industry have made significant efforts to develop an anti-cancer medicine targeting RAS. Despite these intensive efforts, there are no FDA approved anti-RAS drugs at present. For this reason, RAS is perceived as “undruggable”.In 2013, the National Cancer Institute launched the “RAS
initiative” to expand efforts toward the discovery and development of novel medicines for the treatment of RAS-caused cancers. Since then, the initiative has focused on answering the key questions:

Can it be targeted directly or indirectly?

Which effector pathway of RAS is most crucial for cancer initiation and progression?

Are specific mutants or isoforms required to be specifically targeted for effective inhibition?

The enthusiasm generated by the “RAS initiative” has sparked renewed interest by the biotech and pharma industries, which has restarted their own RAS programs.Exhibit
1.RAS signaling pathways involved in human cancer

Source:
Seminars in Cancer Biology 54 (2019) 138–148

Winning
the War Against RAS Oncoproteins. In
the past, many of the RAS-targeting approaches have failed, mainly due to the
chemical structure of the RAS oncoproteins, which lack binding sites (“deep
pockets”) for small inhibitory molecules. Recent advances in drug design along
with increased understanding of RAS structure and function have led to important
developments in anti-RAS therapeutics. Notably, novel inhibitors capable of binding
specific pockets in mutated RAS oncoproteins specifically targeting the G12C
mutation have been discovered.AMG-510 is a first in class KRASG12C inhibitor, that is currently being assessed in a Phase 1/2 (NCT 03600883) to treat adult patients with locally advanced or metastatic KRAS G12C mutant solid tumors. The most recent data was presented at The American Society of Clinical Oncology (ASCO) Annual meeting on June 2019. AMG-510 demonstrated partial response (PR) in 5/10, stable disease (SD) in 4/10 non-small cell lung cancer (NSCLC) patients amounting to disease control in 9/10 patients. The results in 18 colorectal patients were less striking but encouraging showing stable disease in 13 patients. These results have been the most intriguing patient data shown, encouraging for this space with tremendous commercial potential. Another direct RAS inhibitor (KRAS G12C) is MRTX1257, that is currently being assessed in Phase 1/2 (NCT03785249)clinical study. Data is expected in H2 2019.In addition to direct RAS inhibition, rigosertib is a novel benzyl styryl sulfone kinase inhibitor, which acts as a RAS-mimetic. Rigosertib binds to the RAS binding domain (RBD) blocking RAS-RAF-MEK signaling. It is currently being assessed in a Phase 3 clinical study (NCT02562443) for patients with high-risk myelodysplastic syndromes (HR-MDS). Topline data is expected in H2 2019.Today, there is a better understanding of RAS cancer biology, advancements in genomics, and improved molecular biology tools available to drug developers. This could translate into significant progress, which in return, could lead the industry to finally win the long-lasting battle against the RAS-oncogene.

Bringing
the Holy Grail of cancer research
within reach. RAS
is the most commonly mutated oncogene in cancer (approximately 30% of cancer
patients carry genetic mutations in RAS oncogenes). The RAS signal transduction
network is large, complex, and consists of many interconnecting pathways that
play a major role in cellular growth, evasion of apoptosis, and metastasis.Efforts to develop anti-cancer
drugs targeting RAS have contributed greatly to the understanding of RAS
function, biology, and signaling pathways. The discovery of novel RAS inhibitors
with sufficient affinity and selectivity for mutant forms of RAS have demonstrated
promise as potential cancer treatments. Further research will continue to
improve our understanding of the RAS signaling network and shed light into new therapeutic
strategies. In the near future, new approaches and technologies may finally
bring the holy grail of cancer research within reach, converting RAS-oncoproteins
from an “undruggable” target into a “druggable” one.Sources: